Hartwig Steckel

In vitro evaluation of dry powder inhalers II: influence of carrier particle size and concentration on in vitro deposition

Dry powders and their delivery devices are an alternative to pressurized metered-dose inhalers (pMDI) for the administration of aerosols to the lungs. Generally dry powder aerosols are formulated by mixing a cohesive micronized drug with larger carrier particles resulting in an interactive powder mixture. Redispersion of the drug from agglomerates or the carrier surface during inhalation is a critical factor which greatly influences the fine particle fraction (particles<6.4 μm) to be achieved. Two devices, the single-unit-dose Spinhaler™ (Fisons) and the multiple-unit-dose Easyhaler™ (Orion Pharma) were used to investigate the influence of dry powder formulation on the deposition of interactive mixtures. Following the scheme of a 32-factorial design budesonide was mixed with lactose-α-monohydrate varying the lactose sieve fractions and the drug to carrier proportion. The in vitro deposition of these mixtures was determined using a Twin Stage Impinger (Apparatus A, BP 93) and compared to control experiments performed with unsieved drug carrier. Deposition was found to be highly dependent on the dry powder formulation. Fine particle fractions from 10 up to 50% were observed. The Easyhaler™ shows little differences compared to the Spinhaler™ device.

Micronizing of steroids for pulmonary delivery by supercritical carbon dioxide

Abstract The micronization of various drugs is beset with serious problems due to the insufficient brittleness of crystals when using a jet mill. The purpose of this study was to investigate an alternative micronization technique using the aerosol solvent extraction system (ASES). Several steroids, some for systemic and some for administration by inhalation, were dissolved in an organic solvent and sprayed into supercritical carbon dioxide. The resulting particles were characterized with regard to chemical and physical properties. The following steroids were investigated: beclomethasone-17,21-dipropionate, betamethasone-17-valerate, budesonide, dexamethasone-21-acetate, flunisolide, fluticasone-17-propionate, prednisolone and triamcinolone acetonide. The spraying solution contained 1% (w/w) of drug, the solvents were dichloromethane, methanol or a mixture of both. The median particle size of the steroid particles was in most cases lower than 5 μ and consequently within the respirable range. If a surface active ingredient was added to the spraying solution the particle size increased and the contact angle decreased. HPLC-analysis showed no chemical decomposition of the drug during the process but the crystal properties of certain investigated drugs changed. This was proved by use of X-ray diffraction and scanning electron microscopy (SEM). Most of the steroids used could be micronized by means of the ASES-process with a residual dichloromethane content lower than 350 ppm in all cases.

In vitro evaluation of dry powder inhalers. I : drug deposition of commonly used devices

Abstract Inhalation of aerosolized drugs has become the therapy of choice for the treatment of lung diseases. The most commonly used device, the pressurized metered-dose inhaler (pMDI), however, relied on propellants that were found to deplete the ozone layer. To overcome this drawback dry powder inhalers (DPI) have been developed and MDIs with alternative propellants have been introduced recently. Several products are available by now. This study was carried out to evaluate the accuracy of the dose and the theoretically respirable fraction emitted from commonly used DPIs. In vitro measurements were performed using the Twin Impinger (Appendix A, British Pharmacopoiea, 1993 ) and a self constructed Four Stage Impinger at the standard flow rate of 60 l min −1 . Eleven dry powder formulations that are commercially available on the german market were tested with eight dry powder devices: Pulmicort™ and Aerodur™ Turbuhaler™, Intal™ Spinhaler™, Flui™ SCG and Cromolyn™ Orion Inhaler, Sultanol™ Diskhaler™, Flutide™ Diskus™, Atrovent™ with Inhalator M™, Ventilat™ with Inhalator Ingelheim and Buventol™ and Beclomet™ Easyhaler™. As every dry powder inhaler has a specific air flow resistance that limits flow under in vivo conditions, inhaler devices should be tested at corresponding flow conditions in vitro. Though this is not yet reflected in the pharmacopeias, a general consensus can be seen in the scientific literature. Therefore DPIs having a high resistance were tested at 30 l min −1 and those showing a low resistance at 90 l min −1 with the Twin Impinger additionally. Most products were found to emit a fine particle dose of 20–30% of total emitted dose at 60 l min −1 . The results of the Twin Impinger and the Four Stage Impinger were in good agreement. Measurements at increasing flow rates generally resulted in increasing fine particle fractions.

Factors affecting aerosol performance during nebulization with jet and ultrasonic nebulizers

Nebulization of aqueous solutions is a convenient delivery system to deliver drugs to the lungs because it can produce droplets small enough to reach the alveolar region. However, the droplet size might be affected by the changes in the temperature and the concentration of the nebulizing solution in the reservoir during nebulization. In this study, the changes in the droplet size over the nebulization time using a PariBoy air-jet and a Multisonic ultrasonic nebulizer have been studied. The findings were related to changes in the temperature, concentration, surface tension, viscosity and saturated vapour pressure of the nebulizing solution. By using the jet nebulizer, an increase in the droplet size followed by a decrease has been observed. This observation could be attributed to the approx. 7 degrees C reduction of the temperature during the first 2 min in the jet nebulizer reservoir which increased the viscosity of the nebulizing solution. After this initial period of time, the increasing drug concentration induced a reduction of the surface tension and, consequently, a decrease in the droplet size. However, with the ultrasonic nebulizer a temperature increase of approx. 20 degrees C during the first 6 min in the nebulizing solution was observed leading to a decrease in droplet size, viscosity and surface tension and an increasing saturated vapour pressure. This again led to smaller average droplet sizes.

Insulin-micro- and nanoparticles for pulmonary delivery

The pulmonary application of insulin via oral inhalation turned out to be a promising option due to the large surface area and good vascularisation the lung is offering for the systemic delivery of peptides and proteins. To have a systemic effect, inhaled particles need to attain the alveoli and should therefore have a mass median diameter of less than 2 microm. To achieve such a particle size for dry powders spray drying of drug solutions is a common method. In this study, a nano-precipitation of the drug prior to spray drying was carried out using the solvent change method. The produced powders were compared to powder produced out of a solution and to the marketed product Exubera. The Aerolizer device was used representing a simple capsule-based dry powder inhaler. It could be shown that the insulin yield of the precipitation process highly depends on the used pH-value and the amount of non-solvent. Also the particle size after spray drying decreases with increasing amount of non-solvent. Aerodynamic assessment of insulin powders showed that the precipitated insulin particles behave superior to powders spray dried from solution with respect to particles smaller than 2 microm. The deposition pattern of the originator powder delivered with the Exubera device showed significantly lower fine particle fractions and higher residues in comparison to the Aerolizer device. In summary, precipitated insulin particles combined with the delivery from a standard capsule-based inhaler were found to be at least as effective in vitro as the marketed Exubera product. With an optimised powder having an increased particle fraction smaller than 2 microm more insulin may reach the deeper lung. Therefore, a lower dose could be used for an effective diabetic therapy.

Production of chitosan pellets by extrusion/spheronization.

Chitosan pellets were successfully prepared using the extrusion/spheronization technology. Microcrystalline cellulose was used as additive in concentrations from 70 to 0%. The powder mixtures were extruded using water and diluted acetic acid solution in different powder to liquid ratios. The effects on bead formation using water and different acetic acid concentrations and solution quantities were analysed. Also, the morphological and mechanical characteristics of the obtained beads were investigated. With demineralized water as granulation fluid, pellets with a maximum of 50% (m/m) of chitosan could be produced. The mass fraction of chitosan within the pellets could be increased to 100% by using diluted acetic acid for the granulation step.

In-situ-micronization of disodium cromoglycate for pulmonary delivery

Drug particle properties are critical for the therapeutic efficiency of a drug delivered to the lung. Jet-milling, a commonly used technique for micronization of drugs, has several disadvantages such as a non-homogeneous particle size distribution, and unnatural, thermodynamically activated particle surfaces causing high agglomeration. For pulmonary use in a dry powder inhaler, in addition to a small particle size, good de-agglomeration behaviour is required. In this study disodium cromoglycate is prepared in situ in a respirable particle size by a controlled crystallization technique. First the drug is dissolved in water (4%) and precipitated by a solvent change method in the presence of a cellulose ether (hydroxypropylmethylcellulose) as a stabilizing hydrocolloid. By rapidly pouring isopropyl alcohol into the drug solution in a 1:8 (v/v) ratio, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth in the presence of the hydrophilic polymer. This dispersion was spray-dried. The mean particle size of the drug was around 3.5 microm and consequently was in the respirable range. The in-situ-micronized drug powder was tested for its aerodynamic behaviour and compared with jet-milled drug powder and with commercial products using the Spinhaler, the Cyclohaler, and the FlowCaps-Inhaler as model devices. The fine particle fraction (FPF) (<5 microm) was increased from 7% for the jet-milled drug to approximately 75% for the in-situ-micronized drug when the pure drug powder was dispersed without any device. Delivery of the engineered particles via the Spinhaler, the FlowCaps-Inhaler and the Cyclohaler increased the FPF from 11 to 46%, 19 to 51%, and 8 to 40%, respectively.

In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate

Particle properties are decisive for therapeutic efficiency of an inhaled pulmonary drug. Jet-milling as the common way for micronization of inhaled powder drugs shows several disadvantages such as a non-homogeneous particle size distribution and unnatural, thermodynamically-activated particle surfaces causing a high agglomeration behavior. For pulmonary use in a dry powder inhaler (DPI) beside a small particle size, a good de-agglomeration activity is required. In this study, fluticasone-17-propionate (FP) is in-situ prepared in a respirable particle size by a controlled crystallization technique. First, the drug is dissolved in acetone and precipitated by a solvent change method in the presence of a cellulose ether (HPMC) as stabilizing hydrocolloid. By rapidly pouring the drug solution into the polymer-rich water phase, the previously molecularly dispersed drug is associated to small particles and stabilized against crystal growth simultaneously by the presence of the hydrophilic polymer. This dispersion was then spray-dried. The mean particle size of the drug was around 2 microm and consequently in the respirable range. The physico-chemical properties of the in-situ-micronized drug were compared to those of an unmilled and a jet-milled quality. Differences in the X-ray patterns and amorphous parts could be detected for the jet-milled but not for the in-situ-micronized drug. In addition, the aerodynamic behavior of the engineered and the jet-milled FP was analyzed using the FlowCaps inhaler as delivery device and compared to the commercial product Flutide Diskus. The fine particle fraction (FPF) (<5 microm) was increased four-fold from approximately 9% for the jet-milled drug to approximately 40% for the in-situ-micronized drug when the pure drug powder was dispersed with the FlowCaps device.

Solubilization of poorly water-soluble drugs by mixed micelles based on hydrogenated phosphatidylcholine

A remarkable part of newly developed active pharmaceutical ingredients is rejected in early phase development and will never find a way to a patient because of poor water solubility which is often paired with poor bioavailability. Considering such arising solubility problems the development of application vehicles like mixed micelles (MM) is a challenging research topic in pharmaceutical technology. While known classical MM systems are composed of phosphatidylcholine and bile salts, it was the aim of this study to investigate if alternatively developed MM systems were superior in solubilization of different hydrophobic drugs. The novel MM were also comprised of phosphatidylcholine and (contrarily to bile salts) different other suitable surfactants forming binary MM. As model water-insoluble drug substances two benzodiazepines, diazepam and tetrazepam, and the steroid estradiol were chosen. In this study the solubilization capacities of newly developed MM were compared to those of classical lecithin/bile salt MM systems and different other surfactant containing systems. The MM system with sucrose laurate and hydrogenated PC (hPC) at a weight fraction of 0.5 was found to be superior in drug solubilization of all investigated drugs compared to the classical lecithin/bile salt mixed micelles. Further, a polysorbate 80 solution, also at 5%, was inferior with regard to solubilize the investigated hydrophobic drugs. The MM sizes of the favorite developed MM system, before and after drug incorporation, were analysed by dynamic light scattering (DLS) to evaluate the influence of the drug incorporation. Here, the particle sizes, before and after drug incorporation, remained constant, indicating a stable formation of the solubilizate. Further the critical micelle concentration (CMC) of MM before and after drug incorporation was analysed by three different determination techniques. Constant CMC-values could be obtained regardless if diazepam was encapsulated within the MM or unloaded MM were analysed.

Physico-chemical aspects of lactose for inhalation ☆

A dry powder inhaler (DPI) is a dosage form that consists of a powder formulation in a device which is designed to deliver an active ingredient to the respiratory tract. It has been extensively investigated over the past years and several aspects relating to device and particulate delivery mechanisms have been the focal points for debate. DPI formulations may or may not contain carrier particles but whenever a carrier is included in a commercial formulation, it is almost invariably lactose monohydrate. Many physicochemical properties of the lactose carrier particles have been reported to affect the efficiency of a DPI. A number of preparation methods have been developed which have been claimed to produce lactose carriers with characteristics which lead to improved deposition. Alongside these developments, a number of characterization methods have been developed which have been reported to be useful in the measurement of key properties of the particulate ingredients. This review describes the various physicochemical characteristics of lactose, methods of manufacturing lactose particulates and their characterization.